PROJECT SUMMARY Even with currently available antibiotics, bacterial pneumonia is a significant cause of morbidity and mortality in influenza pandemics and epidemics. It is known that T cells are required for elimination of viral infection; however, preliminary studies show that their activation is solely responsible for influenza-induced susceptibility to S. pneumoniae lung infection. On the other hand, resident alveolar macrophages (AMs) are not only essential but also efficacious in pneumococcal clearance. However, influenza infection suppresses the antibacterial function of AMs, which in turn causes susceptibility to secondary infection. Furthermore, preliminary studies indicate that Suppressor Of Cytokine Signaling 1 (SOCS1) is critically involved in influenza- induced suppression of antibacterial immunity. Based on these novel observations, the major goals of this application are to identify cellular and molecular mediators that link T cell activation with AM dysfunction, and to determine how SOCS1 regulates this suppressive process during coinfection. The central hypothesis is that after influenza infection, T cell/SOCS1 modulation of lung cytokine environment results in suppression of AM- mediated innate defenses against S. pneumoniae. It has shown that T cell IFN-? production suppresses bacterial phagocytosis by AMs. Therefore, this application will determine: 1) how T cells induce IFN-?- independent suppression of innate immunity, 2) how T cell-driven immune changes affect AM antibacterial function, and 3) how SOCS1 regulates the crosstalk between T cells and AMs during influenza and S. pneumoniae coinfection. The long-term goal of this research is to identify targets and therapeutics to reverse this susceptibility to secondary pneumonia in humans.